Thienoquinazoline PLK1 Inhibitors With Improved Selectivity and Stability
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Solution Overview
Problem
Current PLK1 inhibitors, such as Onvansertib, while showing promise in clinical studies, face challenges in achieving high selectivity and stability for effective cancer treatment, particularly in tumors like colorectal cancer.
Innovation Solution
Development of 5,6-dihydrothieno[3,4-h]quinazoline compounds and their pharmaceutically acceptable salts, which selectively inhibit PLK1, offering improved inhibitory activity and stability for treating solid tumors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current PLK1 inhibitors like Onvansertib are used, then clinical benefit is achieved in cancer treatment, but selectivity and stability are insufficient for effective treatment
Solution Approach 1:
The patent modifies the chemical structure parameters of PLK1 inhibitors by introducing specific substituents at defined positions (R1-R6 groups with various options like halogen, alkyl, alkoxy, heteroaryl) to optimize the balance between selectivity and treatment efficacy. This structural parameter optimization enables the compound to achieve both high selectivity for PLK1 and improved therapeutic effectiveness.
2Reliability
If current PLK1 inhibitors like Onvansertib are used, then clinical benefit is achieved in cancer treatment, but stability is insufficient for effective treatment
Solution Approach 1:
The patent optimizes molecular stability parameters through strategic selection of chemically stable substituent groups (such as halogen atoms, saturated hydrocarbon groups, and heterocyclic groups) that resist metabolic degradation while maintaining biological activity, thereby achieving both stability and treatment efficacy.
3Power
If compound structure is optimized for better PLK1 inhibition, then inhibitory activity improves, but selectivity may be compromised
Solution Approach 1:
The patent applies local quality optimization by introducing specific functional groups at particular positions (R1-R6) of the core thienoquinazoline structure, where each substituent is carefully selected to enhance inhibitory activity at the target binding site while maintaining overall molecular selectivity through localized structural modifications.
Solution Approach 2:
The patent systematically varies substituent parameters (type, position, and combination of R1-R6 groups) to fine-tune the balance between inhibitory power and selectivity, using structure-activity relationship optimization to achieve high PLK1 inhibition with minimal off-target effects.
Data Source
AI summary
Provided are a series of 5,6-dihydrothieno[3,4-h]quinazoline compounds as represented by formula (P) and pharmaceutically acceptable salts thereof, and the use of the compounds or pharmaceutically acceptable salts thereof in the preparation of solid tumor drugs, such as solid tumor drugs associated with selective PLK1 inhibitors.